Synthesis method of 2-bromo-5-fluoro-4-methoxypyridine

Abstract

The invention discloses a synthesis method of 2-bromo-5-fluoro-4-methoxypyridine, which comprises the following steps: by taking 2-bromo-5-fluoropyridine as a raw material, firstly converting into (2-bromo-5-fluoropyridine-4-yl) boric acid, then converting into 2-bromo-5-fluoro-4-hydroxypyridine, and finally under the action of triphenylphosphine, methanol and diisopropyl azodicarboxylate, carrying out a reaction to obtain 2-bromo-5-fluoro-4-methoxypyridine. The target compound 2-bromine-5-fluoro-4-methoxypyridine is obtained after the reaction is completed. According to the synthesis method, in key steps, triphenylphosphine, methanol and diisopropyl azodicarboxylate are adopted to convert a compound 2-bromo-5-fluoro-4-hydroxypyridine into 2-bromo-5-fluoro-4-methoxypyridine through a Mitsunobu reaction, no isomer by-products are generated, post-treatment and purification are simple, the reaction and time cost is greatly reduced, the yield is ideal, and the method is suitable for industrial production. And the defects of easy generation of isomers, difficult purification and the like in the prior art are avoided.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 2-bromo-5-fluoro-4-methoxypyridine. BACKGROUND

[0002] Pyridine compounds are an important class of heterocyclic compounds, have strong anticancer, antiviral, cardiotonic, antihypertensive and other physiological activities, and are widely used in the research and development of new drugs in the fields of medicine, veterinary medicine and pesticide. Compound 2-bromo-5-fluoro-4-methoxypyridine is an important pyridine compound and also an important molecular building block. As a key intermediate, it is used for the synthesis of a dihydroisoquinolinone derivative in patent WO2022 / 122037, which has high protein-protein interaction inhibition activity on WDR5, and thus can be used for preventing or treating diseases related to WDR5; it is used for the synthesis of a CDK12 inhibitor in patent WO2023091726, which can be used for treating proliferative diseases such as bladder cancer, breast cancer, Ewing's sarcoma, gastric cancer, gastrointestinal cancer, hematological cancer, lung cancer, ovarian cancer, pancreatic cancer, brain cancer and the like. In the prior art, the conventional synthesis route of the compound 2-bromo-5-fluoro-4-methoxypyridine is to use 2-bromo-5-fluoropyridine as a raw material, to convert it into (2-bromo-5-fluoropyridin-4-yl)boronic acid, then into 2-bromo-5-fluoro-4-hydroxypyridine, and finally to react to obtain 2-bromo-5-fluoro-4-methoxypyridine. In this process, the third step of the existing reaction method is prone to produce isomer by-product, which is difficult to purify and has low yield, and therefore, it is of certain significance to develop a new reaction method for this step. SUMMARY

[0003] In view of the deficiencies of the existing synthesis method of 2-bromo-5-fluoro-4-methoxypyridine, the purpose of the present application is to provide a synthesis method of 2-bromo-5-fluoro-4-methoxypyridine, which has the advantages of ideal yield and the like.

[0004] To achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0005] A synthesis method of 2-bromo-5-fluoro-4-methoxypyridine uses 2-bromo-5-fluoropyridine as a raw material, converts it into (2-bromo-5-fluoropyridin-4-yl)boronic acid, then into 2-bromo-5-fluoro-4-hydroxypyridine, and finally obtains the target compound 2-bromo-5-fluoro-4-methoxypyridine under the action of triphenylphosphine, methanol and diisopropyl azodicarboxylate, and the synthesis route is as follows:

[0006]

[0007] Further, the synthesis method of the 2-bromo-5-fluoro-4-methoxypyridine comprises the following steps:

[0008] (1) Compound 1, i.e. 2-bromo-5-fluoropyridine, is dissolved in an organic solvent I, under protection of an inert gas, cooled to -80°C to -50°C, and a lithium diisopropylamide solution is added dropwise, reacted at -80°C to -50°C for 20-40 minutes, then triisopropyl borate is added dropwise while keeping the temperature at -80°C to -50°C, reacted at -80°C to -50°C for 1-3 hours, and after the reaction is completed, post-treatment is performed to obtain compound 2;

[0009] (2) Compound 2 is dissolved in an organic solvent II, cooled to -5°C to 5°C, and an aqueous hydrogen peroxide solution is added dropwise, after the addition is completed, the reaction is warmed to room temperature, and stirred for 10-40 hours, and after the reaction is completed, post-treatment is performed to obtain compound 3, i.e. 2-bromo-5-fluoro-4-hydroxypyridine;

[0010] (3) Compound 3, triphenylphosphine and methanol are dissolved in an organic solvent III, cooled to -80°C to -50°C, and diisopropyl azodicarboxylate is added dropwise, the reaction is warmed to room temperature, and stirred for 8-20 hours, and after the reaction is completed, post-treatment is performed to obtain the target compound 4, i.e. 2-bromo-5-fluoro-4-methoxypyridine.

[0011] Further, in step (1), the organic solvent I is selected from one or more of tetrahydrofuran or diethyl ether or methyl tert-butyl ether.

[0012] Further, in step (1), the lithium diisopropylamide solution is selected from one or more of lithium diisopropylamide solution in n-hexane, lithium diisopropylamide solution in n-ethane or lithium diisopropylamide solution in tetrahydrofuran.

[0013] Further, in step (1), the inert gas is selected from one or more of nitrogen or argon.

[0014] Further, in step (1), the molar ratio of compound 1 to lithium diisopropylamide is 1:1-2.

[0015] Further, in step (1), the molar ratio of compound 1 to compound 2 is 1:1-2.

[0016] Further, in step (1), the mass-volume ratio g / mL of compound 1 to the organic solvent I is 1:5-40.

[0017] Further, in step (1), the post-treatment is as follows: after the reaction is completed, the reaction solution is poured into ice water, hydrochloric acid is used to adjust the pH to 1-2, and then extracted with organic solvent IV. The organic phase is washed with saturated brine, dried, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is purified to obtain compound 2, i.e. (2-bromo-5-fluoropyridin-4-yl)boronic acid.

[0018] Further, in step (1), the organic solvent IV is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane or dichloroethane.

[0019] Further, in step (1), the purification method is selected from one or more of beating, column chromatography, recrystallization or distillation.

[0020] Further, in step (2), the organic solvent II is selected from one or more of dichloromethane, chloroform, trichloromethane, dichloroethane, dichloropropane, trichloroethane.

[0021] Further, in step (2), the molar ratio of compound 2 to hydrogen peroxide is 1:1-4.

[0022] Further, in step (2), the mass-volume ratio g / mL of compound 2 to organic solvent II is 1:5-40. Further, in step (2), the post-treatment is as follows: after the reaction is completed, the reaction solution is slowly poured into a saturated ice anhydrous sodium sulfite solution, stirred for 20-40 minutes to completely quench; the liquid is separated, the aqueous phase is washed with organic solvent V, the acidic aqueous solution is adjusted to pH 1-2, extracted with organic solvent VI, and the organic phase is dried and rotary evaporated to obtain a crude product. The crude product is purified to obtain compound 3, i.e. 2-bromo-5-fluoro-4-hydroxypyridine.

[0023] Further, in step (2), the organic solvent V is selected from one or more of dichloromethane, chloroform, trichloromethane, dichloroethane, dichloropropane, trichloroethane.

[0024] Further, in step (2), the organic solvent VI is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane or dichloroethane.

[0025] Further, in step (3), the organic solvent III is selected from one or more of tetrahydrofuran, diethyl ether or methyl tert-butyl ether.

[0026] Further, in step (3), the mass-volume ratio g / mL of compound 3 to organic solvent III is 1:5-40. Further, in step (3), the molar ratio of compound 3 to triphenylphosphine is 1:1-3.

[0027] Furthermore, in step (3), the molar ratio of compound 3 to methanol is 1:1-3.

[0028] Furthermore, in step (3), the molar ratio of compound 3 to diisopropyl azodicarbonate is 1:1-3.

[0029] Furthermore, in step (3), the post-processing is as follows: after the reaction is completed, the reaction solution is poured into ice water, extracted with organic solvent VII, the organic phases are combined, the organic phases are washed, dried, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product; the crude product is purified to obtain the target compound 4, namely 2-bromo-5-fluoro-4-methoxypyridine.

[0030] Furthermore, in step (3), the organic solvent VII is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane or dichloroethane.

[0031] Furthermore, in step (3), the purification method is selected from one or more of pulping, column chromatography, recrystallization or distillation.

[0032] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0033] This invention proposes a method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine. Using 2-bromo-5-fluoropyridine as a starting material, it is first converted to (2-bromo-5-fluoropyridin-4-yl)boronic acid, then to 2-bromo-5-fluoro-4-hydroxypyridine, and finally, in the presence of triphenylphosphine, methanol, and diisopropyl azodicarbonate, the target compound 2-bromo-5-fluoro-4-methoxypyridine is obtained. In the key step of this synthetic method, triphenylphosphine, methanol, and diisopropyl azodicarbonate are used to convert 2-bromo-5-fluoro-4-hydroxypyridine to 2-bromo-5-fluoro-4-methoxypyridine via the Mitsunobu reaction. This method avoids the generation of isomer byproducts, simplifies post-processing and purification, significantly reduces reaction and time costs, achieves ideal yields, and avoids the drawbacks of existing methods such as the easy generation of isomers and difficult purification. Attached Figure Description

[0034] Figure 1 The 1H NMR spectrum of compound 2 in Example 1;

[0035] Figure 2 The 1H NMR spectrum of compound 3 in Example 1;

[0036] Figure 3 The image shows the 1H NMR spectrum of compound 4 from Example 1. Detailed Implementation

[0037] To make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the described embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0038] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0039] The following examples illustrate the synthesis of 2-bromo-5-fluoro-4-methoxypyridine. Using 2-bromo-5-fluoropyridine as a starting material, it was first converted to (2-bromo-5-fluoropyridin-4-yl)boronic acid, then to 2-bromo-5-fluoro-4-hydroxypyridine, and finally, under the action of triphenylphosphine, methanol, and diisopropyl azodicarbonate, the target compound 2-bromo-5-fluoro-4-methoxypyridine was obtained. The synthetic route is as follows:

[0040]

[0041] The technical solution of the present invention will be further explained and illustrated below through embodiments.

[0042] Example 1

[0043] In this embodiment, the compound 2-bromo-5-fluoro-4-methoxypyridine was synthesized using the following steps:

[0044] (1) Compound 1, 2-bromo-5-fluoropyridine (500.00 g, 2.84 mol, 1.00 eq), was dissolved in tetrahydrofuran (4.0 L). Under nitrogen protection, the solution was cooled to -60 °C, and diisopropylaminolithium solution (2.00 M in THF, 1.85 kmL, 3.69 mol, 1.30 eq) was added dropwise. The reaction was carried out at -60 °C for 30 minutes. Then, triisopropyl borate (694.64 g, 3.69 mol, 1.30 eq) was added dropwise while maintaining the temperature at -60 °C, and the reaction was carried out at -60 °C for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (4.0 L), and the pH was adjusted to 1-2 with hydrochloric acid. The solution was extracted twice with ethyl acetate (3.0 L × 2). The organic phases were combined, washed once with saturated brine (5.0 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was slurried in a mixed organic solvent (500 mL, petroleum ether to ethyl acetate volume ratio of 3:1) to obtain compound 2, namely (2-bromo-5-fluoropyridin-4-yl)boronic acid (weight 614.30 g, purity 98%, yield 96%).

[0045] The 1H NMR spectrum of the obtained compound 2 ((2-bromo-5-fluoropyridin-4-yl)boronic acid) is as follows: Figure 1 As shown, the characterization data is as follows: 1 H NMR (400MHz, dmso) δ8.33 (s, 1H), 7.66 (d, J = 4.1Hz, 1H).

[0046] (2) Compound 2 (600.00 g, 2.73 mol, 1.00 eq) was dissolved in dichloromethane (6.0 L), cooled to 0 °C, and hydrogen peroxide aqueous solution (928.48 g, 3.00 eq, 30.00% weight) was added dropwise. After the addition was complete, the reaction was heated to room temperature and stirred for 12 hours. After the reaction was complete, the reaction solution was slowly poured into a saturated ice-cold anhydrous sodium sulfite solution (7.0 L), and stirred for 30 minutes to completely quench the reaction. The mixture was separated, the aqueous phase was washed with dichloromethane (4.0 L), the pH was adjusted to 1 with 10 M hydrochloric acid aqueous solution, and extracted twice with ethyl acetate (5.0 L × 2). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. The crude product was slurried with petroleum ether (5.0 L) to obtain compound 3, namely 2-bromo-5-fluoro-4-hydroxypyridine (weight 521.10 g, purity 98%, yield 97%).

[0047] The 1H NMR spectrum of the obtained compound 3 (2-bromo-5-fluoro-4-hydroxypyridine) is as follows: Figure 2 As shown, the characterization data is as follows: 1 HNMR (400MHz, DMSO) δ11.96 (s, 1H), 8.22 (d, J = 3.0Hz, 1H), 7.10 (d, J = 6.5Hz, 1H).

[0048] (3) Compound 3 (500.00 g, 2.60 mol, 1.00 eq), triphenylphosphine (819.72 g, 3.13 mol, 1.20 eq), and methanol (100.14 g, 3.13 mol, 1.20 eq) were dissolved in tetrahydrofuran (5.0 L), cooled to -60 °C, and diisopropyl azodicarbonate (684.61 g, 3.39 mol, 1.30 eq) was added dropwise. The reaction mixture was then heated to room temperature and stirred for 12 hours. After the reaction was complete, the reaction solution was poured into ice water (5.0 L), extracted twice with ethyl acetate (4.0 L × 2), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was pulped in a mixed organic solvent (800 mL, petroleum ether to ethyl acetate volume ratio of 5:1), filtered, and the filtrate was collected. The filtrate was then evaporated to dryness, pulped again in petroleum ether (1.0 L) at 0 °C, filtered, and the solid was collected and dried to obtain the target compound 4, namely 2-bromo-5-fluoro-4-methoxypyridine (weight 526.10 g, purity 98%, yield 96%).

[0049] The 1H NMR spectrum of the obtained compound 4 (2-bromo-5-fluoro-4-methoxypyridine) is as follows: Figure 3 As shown, the characterization data is as follows: 1 H NMR (400MHz, CDCl3) δ8.09 (d, J = 2.8Hz, 1H), 7.06–7.01 (m, 1H), 3.93 (d, J = 3.4Hz, 3H).

[0050] Example 2-11

[0051] Examples 2-11 are the same as Example 1, except that the amounts of triphenylphosphine, methanol, diisopropyl azodicarbonate, organic solvent III, and reaction time used in step (3) are adjusted as shown in Table 1.

[0052] Comparative Examples 1-2

[0053] Comparative Examples 1-2 are the same as Example 1, except that the organic solvent III used in step (3) is adjusted, as shown in Table 1.

[0054] The effects of various reaction conditions on the reaction yield in the synthesis of target compound 4 (2-bromo-5-fluoro-4-methoxypyridine) were verified by Examples 1-11 and Comparative Examples 1-2, and the results are shown in Table 1.

[0055] Table 1: Synthesis conditions and results of the examples and comparative examples

[0056]

[0057] As shown in Table 1:

[0058] Comparing Examples 1-3, the reaction effect was already better when the molar ratio of compound 3 to triphenylphosphine was 1.0:1.2.

[0059] Comparative Examples 1 and 4-5 show that the reaction effect is better when the molar ratio of compound 3 to methanol is 1.0:1.2. Comparative Examples 1 and 6-7 show that the reaction effect is better when the molar ratio of compound 3 to diisopropyl azodicarbonate is 1.0:1.3.

[0060] Comparing Examples 1, 8-9 and Comparative Examples 1-2, the reaction can be carried out in solvents tetrahydrofuran, diethyl ether, and methyl tert-butyl ether. Tetrahydrofuran is more effective as a solvent, while toluene and 1,4-dioxane have poorer reaction results as solvents.

[0061] Comparing Examples 1 and 10-11, the reaction time reached 12 hours, and the reaction effect was optimal.

Claims

1. A method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine, characterized in that, The synthetic method uses 2-bromo-5-fluoropyridine as a starting material, first converting it to (2-bromo-5-fluoropyridin-4-yl)boronic acid, then to 2-bromo-5-fluoro-4-hydroxypyridine, and finally, under the action of triphenylphosphine, methanol, and diisopropyl azodicarbonate, the target compound 2-bromo-5-fluoro-4-methoxypyridine is obtained. The synthetic route is as follows:

2. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 1, characterized in that, The synthesis method includes the following steps: (1) Compound 1, namely 2-bromo-5-fluoropyridine, was dissolved in organic solvent I. Under inert gas protection, the temperature was lowered to -80°C to -50°C, and diisopropylaminolithium solution was added dropwise. After reacting at -80°C to -50°C for 20-40 minutes, triisopropyl borate was added dropwise while maintaining the temperature at -80°C to -50°C. The reaction was carried out at -80°C to -50°C for 1-3 hours. After the reaction was completed, post-treatment was performed to obtain compound 2. (2) Dissolve compound 2 in organic solvent II, cool to -5℃ to 5℃, add hydrogen peroxide aqueous solution dropwise, after the addition is complete, heat the reaction to room temperature and stir for 10-40 hours, and perform post-treatment after the reaction is completed to obtain compound 3, namely 2-bromo-5-fluoro-4-hydroxypyridine. (3) Compound 3, triphenylphosphine, and methanol were dissolved in organic solvent III, cooled to -80℃ to -50℃, and diisopropyl azodicarbonate was added dropwise. The reaction was heated to room temperature and stirred for 8-20 hours. After the reaction was completed, post-treatment was performed to obtain target compound 4, namely 2-bromo-5-fluoro-4-methoxypyridine.

3. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 2, characterized in that, In step (1), The organic solvent I is selected from one or more of tetrahydrofuran, diethyl ether, or methyl tert-butyl ether; The diisopropylaminolithium solution is selected from one or more of the following: diisopropylaminolithium dissolved in n-hexane solution, diisopropylaminolithium dissolved in n-hexane solution, or diisopropylaminolithium dissolved in tetrahydrofuran solution. The inert gas is selected from one or more of nitrogen or argon; The molar ratio of compound 1 to lithium diisopropylaminodimethylamine is 1:1-2; The molar ratio of compound 1 to compound 2 is 1:1-2; The mass-to-volume ratio of compound 1 to organic solvent I is 1:5-40 (g / mL).

4. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 2, characterized in that, In step (1), The post-processing is as follows: after the reaction is completed, the reaction solution is poured into ice water, the pH is adjusted to 1-2 with hydrochloric acid, and the solution is extracted with organic solvent IV. After the organic phases are combined, the solution is washed with saturated brine, dried, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is purified to obtain compound 2, namely (2-bromo-5-fluoropyridin-4-yl)boronic acid.

5. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 4, characterized in that, In step (1), The organic solvent IV is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane; The purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

6. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 2, characterized in that, In step (2), The organic solvent II is selected from one or more of dichloromethane, chloroform, trichloromethane, dichloroethane, dichloropropane, and trichloroethane; The molar ratio of compound 2 to hydrogen peroxide is 1:1-4; The mass-to-volume ratio of compound 2 to organic solvent II is 1:5-40 (g / mL). The post-processing is as follows: After the reaction is completed, the reaction solution is slowly poured into a saturated ice-cold anhydrous sodium sulfite solution and stirred for 20-40 minutes to completely quench the reaction; the aqueous phase is separated, washed with organic solvent V, the pH is adjusted to 1-2 with an acidic aqueous solution, extracted with organic solvent VI, and the organic phase is dried and evaporated to obtain the crude product; the crude product is purified to obtain compound 3, namely 2-bromo-5-fluoro-4-hydroxypyridine.

7. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 6, characterized in that, In step (2), The organic solvent V is selected from one or more of dichloromethane, chloroform, trichloromethane, dichloroethane, dichloropropane, and trichloroethane; The organic solvent VI is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

8. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 2, characterized in that, In step (3), The organic solvent III is selected from one or more of tetrahydrofuran, diethyl ether, or methyl tert-butyl ether; The mass-to-volume ratio of compound 3 to organic solvent III is 1:5-40 (g / mL); The molar ratio of compound 3 to triphenylphosphine is 1:1-3; The molar ratio of compound 3 to methanol is 1:1-3; The molar ratio of compound 3 to diisopropyl azodicarbonate is 1:1-3.

9. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 2, characterized in that, In step (3), The post-processing is as follows: after the reaction is completed, the reaction solution is poured into ice water and extracted with organic solvent VII. The organic phases are combined, washed, dried, and filtered. The filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is purified to obtain the target compound 4, namely 2-bromo-5-fluoro-4-methoxypyridine.

10. The method for synthesizing 2-bromo-5-fluoro-4-methoxypyridine according to claim 9, characterized in that, In step (3), The organic solvent VII is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane; The purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

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